Methods for treating Parkinson&#39;s disease using optically pure (−)-bupropion

ABSTRACT

Methods and compositions are disclosed utilizing the optically pure (−)-isomer of bupropion, which is a potent drug for treating, Parkinson&#39;s disease.

This application is divisional of Ser. No. 09/238,812, filed Jan. 28,1999 U.S. Pat. No. 6,110,973 which claims priority to provisionalapplication no. 60/072,931, field Jan. 29, 1998.

1. FIELD OF THE INVENTION

This invention relates to methods of treatment and pharmaceuticalcompositions employing the compound (−)-bupropion.

2. BACKGROUND OF THE INVENTION

2.1. STERIC RELATIONSHIPS AND DRUG ACTION

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes D and L or R and S are usedto denote the absolute configuration of the molecule about its chiralcenter(s). The prefixes (+) and (−) or d and 1 are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or 1 meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they aremirror images of one another. A specific stereoisomer may also bereferred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric or racemic mixture.

Stereochemical purity is of importance in the field of pharmaceuticals,where 16 of the 20 most prescribed drugs exhibit chirality. A case inpoint is provided by the L-form of the β -adrenergic blocking agent,propranolol, which is known to be 100 times more potent than theD-enantiomer.

Furthermore, optical purity is important-since certain isomers mayactually be deleterious rather than simply inert. For example, it hasbeen suggested that the D-enantiomer of thalidomide was a safe andeffective sedative when prescribed for the control of morning sicknessduring pregnancy, while the corresponding L-enantiomer was a potentteratogen.

Bupropion is available only as a racemic mixture called Wellbutrin® andWellbutrin SR® (for depression), and Zyban|® (to achievesmoking-cessation). That is, bupropion is available as a mixture ofoptical isomers, called enantiomers. The racemic mixture of bupropionwhich is commercially available is administered as a hydrochloride salt.In addition, European Patent Application No. 84101070.5 published Sep.12, 1984 discloses the benefits of bupropion maleate over bupropionhydrochloride.

Bupropion is used primarily in the treatment-of depression, which alongwith mania, falls under the heading of affective disorders.Particularly, bupropion is used in patients who do not respond to, orcannot tolerate other antidepressants, such as the tricyclic agents ormonoamine oxidase inhibitors. Additionally, the racemic mixture ofbupropion is useful in the management of patients with bipolar andschizo-affective disorder, attention-deficit disorder, psycho-sexualdysfunction, bulimia and-other eating disorders, and Parkinson'sdisease.

Affective disorders, including major depression, and the bipolar,manic-depressive illness, are characterized by changes in mood as theprimary clinical manifestation. Major depression is the most common ofthe significant mental illnesses, and it must be distinguishedclinically from periods of normal grief, sadness and disappointment, andthe related dysphoria or demoralization frequently associated withmedical illness. Depression is characterized by feelings of intensesadness, and despair, mental slowing and loss of concentration,pessimistic worry, agitation, and self-deprecation. Physical changes canalso occur, including insomnia, anorexia, and weight loss, decreasedenergy and libido, and disruption of hormonal circadian rhythms. Oftenthe condition responds well to tricyclic or related antidepressantdrugs, monoamine oxidase inhibitors, or in resistant cases or severedisease, to electro-convulsive shock treatment.

Mania, as well as depression, is characterized by changes in mood as theprimary symptom. Either of these two extremes of mood may be accompaniedby psychosis with disordered thought and delusional perceptions.Psychosis may have, as a secondary symptom, a change in mood, and it isthis overlap with depression that causes much confusion in diagnosis.Severe mood changes without psychosis frequently occur in depression andare often accompanied by anxiety.

Through an unknown mechanism of action, bupropion has been demonstratedto be an effective treatment in depression in short-term and longerduration clinical studies. The racemic mixture of bupropion has beenreported to have an antidepressant activity equal to amitriptyline, thetricyclic antidepressant, with fewer anticholinergic, sedative andcardiovascular side effects than with amitriptyline.

Parkinson's disease, independent of a specific etiology, is a chronic,progressive central nervous system disorder which usually appearsinsidiously in the latter. decades of life. The disease produces aslowly increasing disability in purposeful movement. It is characterizedby four major clinical features of tremor, bradykinesia, rigidity and adisturbance of posture. Often patients have an accompanying dementia. Inidiopathic Parkinsonism, there is usually a loss of cells in thesubstantia nigra, locus ceruleus, and other pigmented neurons of thebrain, and a decrease of dopamine content in nerve axon terminals ofcells projecting from the substantia nigra. The understanding thatParkinsonism is a syndrome of dopamine deficiency and the discovery oflevodopa as an important drug for the treatment of the disease were thelogical culmination of a series of related basic and clinicalobservations, which serves as the rationale for drug treatment.

When the racemic mixture of bupropion is used to treat Parkinson'sdisease, an improvement in gait, akinesia, and postural stability wereobserved, with tremor improving in those patients experiencing the mostglobal benefit. Concomitant depression was alleviated in several of thepatients reporting the condition.

Attention-deficit disorder (“ADD”) is a common behavioral learningdisorder in children which adversely affects school performance andfamily relationships. Symptoms and signs include hyperactivity (e.g.,ADDH and AD/HD, DSM-IV), impulsivity, emotional lability, motorincoordination and some perceptual difficulties. Treatment has includedpsychostimulants, which while effective are controversial, and may causetroubling side effects such as dysphoria, headache and growthretardation. Other drugs, including the tricyclic antidepressants,appear to improve attention, but may be less effective than thepsychostimulants.

Bupropion has been shown to be effective in children withattention-deficit disorder or conduct disorder thus improving thesymptoms of anxiety, hostility and uncooperativeness, antisocialbehavior, as well as eating disturbances. The drug has also demonstratedactivity in cases of psycho-sexual dysfunction and bulimia. However,bupropion is contra-indicated in patients with a seizure disorder, or acurrent or prior diagnosis of bulimia or anorexia nervosa characterizedby a disturbed sense of body image and abnormally high anxiety aboutweight gain.

It has been suggested that the racemic mixture of bupropion could beused to assist in weight loss. Treatment with bupropion is consistentlyassociated with a lack of weight gain. Also bupropion reduces episodesof.binge eating and purging. Although the mechanism by which buprop'ioncauses weight loss is uncertain, an increase in the activity of thepatient may play some part together with subtle changes in food intakeand metabolism.

The causes of excess body weight and/or obesity are complex; however, acommon denominator in the overweight person's diet is a caloric intakewhich exceeds that person's body expenditures. One method of treating aperson who is overweight and/or obese is to restrict that person'scaloric intake, in combination with an exercise regimen. This method maybe limited in its effectiveness since many overweight or obese peoplehave developed eating and activity patterns which are counterproductiveto achieving weight reduction. Another method to treat overweight orobese patients is to administer appetite suppressant drugs inconjunction with a weight reduction program. The drawback to this methodis that many appetite suppressant drugs produce undesirable adverseeffects which limit their usefulness.

The racemic mixture of bupropion, in addition to its use in thetreatment of depression and the other above-mentioned disorders, hasbeen shown to have a wide spectrum of action which includes:

Treatment of the effects of ethanol (U.S. Pat. No. 4,393,078)

Treatment of Tardine Dyskinesia (U.S. Pat. No. 4,425,363)

Treatment of Minimal Brain Dysfunction (U.S. Pat. No. 4,435,449)

Treatment of amelioration of prostate hypertrophy and sexual dysfunction(U.S. Pat. No. 4,835,147)

Treatment of psychostimulant addiction (U.S. Pat. No. 4,935,429)

Treatment of Psychosexual Dysfunction (U.S. Pat. No. 4,507,323)

Methods of Reducing Cholesterol (U.S. Pat. No. 4,438,138)

Methods of assisting weight loss (U.S. Pat. No. 4,895,845)

The racemic mixture of bupropion has been shown to have certainadvantages over other antidepressant drugs. For example, bupropion doesnot inhibit monoamine oxidase, or block the reuptake of serotonin. Attherapeutic concentrations, the compound presumably does not bind toadrenergic, dopamine, GABA, histamine, muscarinic, serotonin, orimipramine binding sites. While its specific neurochemicalantidepressant action is unknown, it does have a relatively weak effecton blocking the reuptake of dopamine, and it appears to reducenorepinephrine metabolism.

While the racemic mixture of bupropion has advantages,. it also hasdisadvantages. Among these disadvantages are adverse effects in additionto those described above. The most serious adverse effect associatedwith the racemic mixture of bupropion is the increased incidence ofseizures. In addition, other frequently reported adverse effectsassociated with the use of racemic bupropion include nausea, vomiting,excitement, agitation, blurred vision, restlessness, postural tremor,and some hallucinations/confusional states with the potential for abuse.Other adverse or side effects associated with the racemic mixture ofbupropion include but are not-limited to anxiety, insomnia, headachesand/or migraines, dry mouth, constipation, tremor, sleepingdisturbances, dermatologic problems (e.g., rashes), neuropsychiatricsigns and symptoms (e.g.; delusions and paranoia), and weight loss gain.See, the Physician's. Desk References® (1998). These effects are doselimiting in a number of patients. In Parkinsonian patients, the adverseeffects can be the particular toxicity of the racemic mixture ofbupropion, or the result of a drug interaction (as most patients werereceiving concomitant levodopa).

Thus, it is desirable to find a compound with the advantages of theracemic mixture of bupropion without the above-described disadvantages.

3. SUMMARY OF THE INVENTION

The active compound of compositions and methods disclosed herein is anoptical isomer of the compound bupropion which is described in U.S. Pat.Nos. 5 3,819,706 and 3,885,046. Chemically, this isomer is(−)-2-(tertbutylamino)-3′-chloropropiophenone or(−)-1-(3-chlorophenyl)-2[(1,1-dimethyl-ethyl)amino]-1-propanone. Thisisomer will hereinafter be referred to as “(−)-bupropion”, which alsoincludes the substantially optically pure (−)-bupropion isomer.

It has now been discovered that the optically pure (−)-isomer ofbupropion is an effective antidepressant which is useful in treatingdepression in humans. In accordance with the present invention,(−)-bupropion can be used to treat depression while avoiding adverseeffects including but not limited to seizures, agitation, dry mouth,insomnia, headache/migraine, nausea, dizziness, tachycardia, vomiting,constipation, and tremor associated with the racemic mixture ofbupropion. It has also been discovered that (−)-bupropion andpharmaceutical compositions containing optically pure (−)-bupropion areuseful in treating weight gain or obesity. Furthermore, it has beendiscovered that the optically pure (−)-isomer of bupropion is useful inthe treatment of Parkinson's disease. In addition, it has been foundthat the optically pure (−)-isomer of bupropion is useful in thetreatment of other disorders including but not limited to bipolardisorders, attention-deficit disorders, conduct. disorders,psycho-sexual dysfunction, bulimia, eating disorders and specific foodcravings.

The present invention also includes methods for treating theabove-described conditions in a human while avoiding adverse effectsthat are associated with the racemic mixture of bupropion, byadministering the optically pure (−)-isomer of bupropion to said human.

4. DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method of treating depression in ahuman while avoiding the concomitant liability of adverse effectsassociated with the administration of racemic. bupropion which comprisesadministering to said human in need of antidepressant therapy, an amountof (−)-bupropion or a pharmaceutically acceptable salt thereof,substantially free of its (+)-stereoisomer, said amount being sufficientto alleviate depression, but insufficient to cause adverse effectsassociated with racemic bupropion.

The present invention also encompasses pharmaceutical compositions forthe treatment of humans which comprises a therapeutically effectiveamount of (−)-bupropion or a pharmaceutically acceptable salt thereof,substantially free of its (+)-stereoisomer, and a pharmaceuticallyacceptable carrier. Preferred pharmaceutical. compositions are thosewhich have a means for controlled sustained release of the activeingredient, (−)-bupropion.

The present invention further encompasses a method of treatingParkinson's disease in a human while avoiding the concomitant liabilityof adverse effects associated with the administration of racemicbupropion, which comprises administering to said human suffering fromParkinson's disease, an amount of (−)-bupropion, or a pharmaceuticallyacceptable salt thereof, substantially free of its (+)-stereoisomer,said amount being sufficient to alleviate said condition, but.insufficient to cause. adverse effects associated with administration ofracemic bupropion.

Further, the present invention encompasses a method of treating obesityor weight gain in a human, which comprises administering to said humanin need of a reduction in weight, an amount of (−)-bupropion or apharmaceutically acceptable salt thereof, substantially free of its(+)-stereoisomer, said amount being sufficient to reduce weight orprevent weight gain, but insufficient to cause adverse effectsassociated with administration of racemic bupropion.

The present invention also encompasses a method of treating disordersincluding, but not limited to, bipolar disorders, attention-deficitdisorders, conduct disorders, psycho-sexual dysfunction, bulimia, eatingdisorders and specific food cravings in humans while avoiding theconcomitant liability of adverse affects associated with theadministration of racemic bupropion, which comprises administering to ahuman in need of such therapy a therapeutically effective amount of(−)-bupropion, or a pharmaceutically acceptable salt thereof,substantially free of its (+)-stereoisomer.

The racemic mixture of bupropion (i.e., approximately a 50:50 mixture ofits two enantiomers) causes antidepressant activity and provides therapyand/or reduction of symptoms in a variety of conditions and disorders;however, this racemic mixture, while offering the expectation ofefficacy, causes a broad range of adverse effects. Utilizing theoptically pure (−)-isomer of bupropion results in clearer dose-relateddefinitions of efficacy, diminished adverse effects, and-accordingly animproved therapeutic index. It is therefore, more desirable to use the(−)-isomer of bupropion for the conditions, described herein.

The term “adverse effects” as used herein includes, but is not limitedto seizures, dry mouth, insomnia, dizziness, restlessness, anxiety,agitation, headache/migraine, nausea/vomiting, constipation, tremor,delusions, tachycardia, hallucinations, psychotic episodes, blurredvision, confusion, paranoia, rashes and sleep disturbances.

The term “substantially free of the (+)-stereoisomer” as used hereinmeans that the composition contains a greater proportion of the(−)-isomer of bupropion in relation to the (+)-isomer of bupropion. In apreferred embodiment the term “substantially free of its (+)-isomer” asused herein means that the composition contains at least 90% by weightof (−)-bupropion and 10% by weight or less of (+)-bupropion; or morepreferably about 95% by weight of (−)-bupropion and 5% or less of its(+)-isomer. These percentages are based on the total amount of bupropionpresent in the composition; In the most preferred embodiment the term“substantially free of the (+)-stereoisomer” means that the compositioncontains approximately 99% by weight of (−)-bupropion, and 1% or less ofthe (+)-bupropion. In another preferred embodiment, the term“substantially free of its (+)-stereoisomer” as used herein means thatthe composition contains greater than 99% by weight of the (−)-isomer ofbupropion, again based on the total amount of bupropion present. Theterms “substantially optically pure (−)-isomer of bupropion,” “opticallypure (−)-isomer of bupropion” and “(−)-isomer of bupropion” are alsoencompassed by the above-described amounts.

The term “a method of treating depression” as used herein means relieffrom the symptoms of depression which include, but are not limited tochanges in mood, feelings of intense sadness and despair, mentalslowing, loss of concentration, pessimistic worry, agitation, andself-deprecation. Physical changes may also be relieved, includinginsomnia, anorexia and weight loss, decreased energy and libido, and thereturn of normal hormonal circadian rhythms.

The term “attention deficit disorder” (ADD) and “attention deficitdisorder with hyperactivity” (ADDH), DSM-III, or attentiondeficit/hyperactivity disorder (AD/HD), DSM-IV are used herein mean inaccordance with the accepted meanings.

The term “treating Parkinson's disease” as used herein means relief fromthe symptoms of Parkinson's disease which include, but are not limitedto tremor, bradykinesia, rigidity, and a disturbance of posture.

The term “treating obesity or weight gain in a human” as used hereinmeans reduction of weight or relief from being overweight or gainingweight due to extensive consumption of food and other factors includingmetabolism disorders.

4.1. SYNTHESIS OF OPTICALLY PURE BUPROPION

The synthesis of the (−)-isomer of bupropion may start from readilyavailable 3-chloropropiophenone (1). Reaction of (1) with a(2R,3R)-(+)-dialkyl tartrate such as (+)-dimethyl or diethyl tartrate inthe presence of an acid catalyst such as methanesulfonic acid gives thechiral acetal (2) according to Castaldi (G. Castaldi, et al., J. Org.Chem. 1987, 52: 3018). Steroselective bromination with bromine in carbontetrachloride, or alternatively ethyl acetate, then produces thecorresponding bromoacetal (3) as the major product according to theabove-referenced procedure developed by Castaldi and co-workers. Thebromoacetal (3) is purified by column chromatography to yield theoptically pure bromoacetal (3) which is then hydrolyzed in the presenceof an acid to afford the bromoketone (4). Treatment of the bromoketone(4) with tert-butylamine, followed by reaction with anhydrous hydrogenchloride, then produces optically pure (−)-bupropion hydrochloride (5)after recrystallization. See the scheme below.

Alternatively, the optically pure isomers of bupropion can be preparedasymmetrically according to the procedures reported by Musso et al.,“Synthesis and Evaluation of the Antidepressant Activity of theEnantiomers of Bupropion”, Chirality 5:495-500 (1993) which isincorporated herein by reference in its entirety.

In addition to the above-described methods the stereoisomers ofbupropion may be obtained by resolutions of a mixture of enantiomers ofbupropion using conventional means such as an optically active resolvingagent; see, for example, “Stereochemistry of Carbon Compounds”, by E. L.Eliel (McGraw-Hill, N.Y., 1962), and S. H. Wilen, p. 268 in “Tables ofResolving Agents and Optical Resolutions” (E. L. Eliel, Ed., Univ. ofNotre Dame Press, Notre Dame, Ind. 1972).

The magnitude of a prophylactic or therapeutic dose of (−)-bupropion inthe acute or chronic management of disease will vary with the severityof the condition to be treated and its route of administration. The doseand dose frequency will also vary according to the age, weight,condition and response of the individual. patient. In general, therecommended daily dose range for the conditions described herein lieswithin the range of from about 10 mg to about 750 mg per day, generallydivided equally into doses given three or four times a day. Preferably,a daily dose range should be between 50 mg-and 600 mg per day, usuallydivided equally into a three or four times a day dosing. Mostpreferably, a daily dose range should be between 60 mg and 450 mg perday, usually divided equally into a three times or a four times a daydosing. It may be necessary to use dosages outside these ranges in somecases. The physician will know how to increase, decrease or interrupttreatment based upon patient response. The various terms described abovesuch as “said amount being sufficient to alleviate said depression”,“said amount being sufficient to alleviate said condition” when saidcondition is Parkinson's Disease, “said amount being sufficient toreduce weight or weight gain”, “said amount being sufficient to achieveweight loss” and “therapeutically effective amount” are encompassed bythe above-described dosage amounts and dose frequency schedule.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of (−)-bupropion. For example, oral,rectal, parenteral, transdermal, subcutaneous, intrathecal,intramuscular and the like may be employed as appropriate. Dosage formsinclude tablets, coated tablets, caplets, capsules, troches,dispersions, sustained release formulations, suspensions, solutions,patches and the like.

The pharmaceutical compositions of the present invention comprise the(−)-isomer of bupropion as active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm “pharmaceutically acceptable salts” refers to salts preparedfrom-pharmaceutically acceptable non-toxic acids including inorganicacids and organic acids.

Since the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids includinginorganic and organic acids. Such acids include maleic, acetic,benzene-sulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Particularly preferred arehydrobromic, hydrochloric, phosphoric, and sulfuric acids.

The pharmaceutical compositions of the present invention includecompositions suitable for oral, rectal, and parenteral administration(including subcutaneous, intrathecal, intramuscular, and intravenous),although the most suitable route in any given case will depend on thenature and severity of the condition being-treated. The 'most preferredroute of the present invention is the oral route. They may beconveniently presented in unit dosage form and prepared by any of themethods well-known in the art of pharmacy.

In the case where an oral composition is employed, a suitable dosagerange, for use is, e.g., from about 10 mg to about 750 mg per day,generally divided equally into a three times a day dosing, preferablyfrom about 50 mg to about 600 mg per day, generally divided equally intoa three times a day dosing and most preferably-from about 60 mg to about450 mg per day, generally divided equally into a three times a daydosing. Patients may be upward titrated from below to within this doserange to a satisfactory control of symptoms as appropriate.

In practical use, (−)-bupropion can be combined as the active ingredientin intimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending on the form of preparation desired foradministration, e.g., oral or parenteral (including intravenousinjections or infusions). In preparing the compositions for oral dosageform, any of the usual-pharmaceutical media may be employed, forexample, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, for example, suspensions, elixirs and solutions; oraerosols; or carriers such as starches, sugars, microcrystallinecellulose, stabilizers, diluents, granulating agents, lubricants,binders, fillers, disintegrating agents and the like in the case of oralsolid preparations such as, powders, capsules and tablets, with thesolid oral preparations being preferred over the liquid preparations.The preferred solid oral preparation is tablets. The most preferredsolid oral preparation is coated tablets. Because of their ease ofadministration tablets and capsules represent the most advantageous oraldosage unit form, in which case solid-pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

Pharmaceutical stabilizers may also be used to stabilize compositionscontaining (−)-bupropion or salts thereof; acceptable stabilizersincluding but are not limited 25 to L-cysteine hydrochloride, glycinehydrochloride, malic acid, sodium metabsulfite, citric acid, tartaricacid and L-cysteine dihydrochloride. See, e.g., U.S. Pat. No. 5,358,970which is incorporated herein by reference.

In addition to the common dosage forms set-but above, the compounds ofthe present invention may also be administered by controlled release orsustained release means and/or delivery devices such as those describedin U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200,4,008,719, 4,687,660,and 4,769,027, the disclosures of which are herebyincorporated by reference. Preferred controlled release or sustainedreleased tablets for-use with (−)-bupropion are described in U.S. Pat.No. 5,427,798 which is incorporated herein by reference.

Pharmaceutical compositions of the present invention suitable for oral-administration may be presented as discrete units such as capsules,cachets, or tablets or aerosol sprays, each containing a predeterminedamount of the active ingredient, as a powder or granules or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any of the methods of pharmacy but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. For example, a tablet may beprepared by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas powder or granules, optionally mixed with a binder, filler,lubricant, inert diluent, and/or surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent. Desirably,each tablet contains from about 10 mg to about 250 mg of the activeingredient, and-each cachet or capsule contains from about 10 mgto.about 250 mg of the active-ingredient. Most preferably, the tablet,cachet or capsule contains one of four dosages: about 50 mg, about 75mg, about 100 mg and about 150 mg of active ingredient.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the compound and compositions ofthe present invention. It will be apparent to those skilled in the artthat many modifications, both to materials and methods, may be practicedwithout departing from the purpose and interest of this invention.

All temperatures-are in degrees Celsius.

5. EXAMPLES 5.1. EXAMPLE 1

ORAL FORMULATION Coated Tablets: Formula Quantity per Tablet (mg.)(-)-bupropion 75 Lactose 125 Corn Starch 5.0 Water (per thousandTablets) 30.0 ml* Magnesium Stearate 0.5 Corn Starch 25.0 * The waterevaporates during manufacture.

The active ingredient is blended with the lactose until a uniform blendis formed. The smaller quantity of corn starch is blended with asuitable quantity of water to form a corn starch paste. This is thenmixed with said uniform blend until a uniform wet mass is formed. Theremaining corn starch is added to the resulting wet mass and mixed untiluniform granules are obtained. The granules are then screened through asuitable milling machine, using a ¼ inch stainless steel screen. Themilled granules are then dried in a suitable drying oven until thedesired moisture content is obtained. The dried granules are then milledthrough a suitable milling machine using ¼ mesh stainless steel screen.The magnesium stearate is then blended and the resulting mixture iscompressed into tablets of desired shape, thickness, hardness anddisintegration. Tablets are coated by standard aqueous or nonaqueoustechniques.

5.2. EXAMPLE 2

ORAL FORMULATION Capsules: Quantity per capsule in mg. Formula A B CActive ingredient 25 50 75 (-)-bupropion Lactose 149.5 124.5 374 CornStarch 25 25 50 Magnesium Stearate 0.5 0.5 1.0 Compression Weight 200.0200.0 500.0

The active ingredient, (−)-bupropion, lactose, and corn starch areblended until uniform; then the magnesium stearate is blended into theresulting powder. The resulting mixture is encapsulated into suitablysized two-piece hard gelatin capsules.

5.3. EXAMPLE 3

ORAL FORMULATION Tablets Quantity per Tablet in mg. Formula A B C Activeingredient, 20 40 100 (-)-bupropion lactose BP 134.5 114.5 309.0 starchBP 30.0 30.0 60.0 Pregelatinized Maize Starch BP 15.0 15.0 30.0magnesium stearate 0.5 0.5 1.0 Compression Weight 200.0 200.0 500.0

The active ingredient is sieved through a suitable sieve and blendedwith lactose, starch, and pregelatinized maize starch. Suitable volumesof purified water are added and the powders are granulated. Afterdrying, the granules are screened and blended with the magnesiumstearate. The granules are then compressed into tablets using punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to lactose or the compression weight and using punchesto suit.

5.4. EXAMPLE 4

Sustained Release Formulation (Tablet) FORMULA QUANTITY PER TABLET (mg)(-)-bupropion hydrochloride 100 Contramid ® crosslinked amylose 98.8Cysteine hydrochloride 7.5 Magnesium stearate 1.2

(−)-Bupropion Hydrochloride is formulated using Contramid® (Labopharm,Inc, Quebec) technology. The formulation is prepared by blending theingredients above (dry) and compressing into tablets. Alternatively, theingredients can be formulated using wet granulation technology known inthe art. (See Example 1).

5.5. EXAMPLE 5

Sustained Release Formulation (Tablet) FORMULA QUANTITY PER TABLET (mg)Contramid ® crosslinked amylose 98.8 Cysteine hydrochloride 7.5(−)-bupropion hydrochloride 75 Magnesium stearate 1.2

(−)-Bupropion Hydrochloride is formulated using Contramid® (Labopharm,Inc, Quebec), technology. The formulation is prepared by blending theingredients above (dry) and compressing into tablets. Alternatively, theingredients can be formulated using wet granulation technology known inthe art. (See Example 1).

5.6. EXAMPLE 6

FORMULA QUANTITY PER TABLET (mg) (-)-bupropion hydrochloride 150Diffutab ® hydrophilic 100 polymer mixture Microcrystalline cellulose100 Cysteine hydrochloride 7.5 Magnesium stearate 4

(−)-Bupropion Hydrochloride is formulated using Diffutab® (Eurand,Microencapsulation, S.A. of Switzerland) technology. The formulationcomponents are dry blended and directly compressed into tablets orformulated using wet granulation technology.

The embodiments of the present invention described above are intended tobe merely exemplary and those skilled in the art will recognize, or beable to ascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. All suchequivalents are considered to be within the scope of the presentinvention and are covered by the following claims.

The contents of all references described herein are hereby incorporatedby reference.

Other embodiments are within the following claims.

What is claimed is:
 1. A method of treating Parkinson's disease in ahuman while avoiding the concomitant liability of adverse effectsassociated with the administration of racemic bupropion, which comprisesadministering to said human in need of treatment for Parkinson'sdisease, a therapeutically effective amount of (−)-bupropion or apharmaceutically acceptable salt thereof, substantially free of its(+)-stereoisomer.
 2. The method of claim 1 wherein said amount issufficient to alleviate said Parkinson's disease, but insufficient tocause said adverse effects associated with administration of racemicbupropion.
 3. The method of claim 1 wherein (−)-bupropion isadministered by intravenously, transdermally, or orally.
 4. The methodof claim 3 wherein (−)-bupropion is administered orally as a tablet or acapsule.
 5. The method of claim 1 wherein the amount administered isfrom about 10 mg to about 750 mg.
 6. The method of claim 5 wherein theamount administered is from about 50 mg to about 600 mg.
 7. The methodof claim 6 wherein the amount administered is from about 60 mg to about450 mg.
 8. The method of claim 1 wherein the amount of (−)-bapropion ora pharmaceutically acceptable salt thereof is greater than approximately90% by weight of the total amount of bupropion.
 9. The method of claim 1wherein the amount of (−)-bupropion or a pharmaceutically acceptablesalt thereof, substantially free of its (+)-stereoisomer, isadministered together with a pharmaceutically acceptable carrier. 10.The method according to claim 1 wherein (−)-bupropion is administered asthe hydrochloride salt.
 11. The method of claim 1 wherein (−)-bupropionis administered in a sustained or controlled release formulation.